This invention is in the field of anthracycline chemistry. More particularly it concerns derivatives of the anthracyclines, doxorubicin and daunorubicin, that are useful as antitumor agents.
Daunorubicin is used for the treatment of certain leukemias. Doxorubicin (adriamycin) is one of the most useful anticancer drugs in use at this time. Doxorubicin is a principle agent in the treatment of an unusually wide number of solid tumors and leukemias. Regrettably, many patients with these tumors fail to respond and essentially no patients with certain serious tumor types (colon cancer, melanoma) are successfully treated. Additionally, in some patients chronic adriamycin treatment produces irreversible heart damage that can be fatal if continued. Thus, there is great need for analogues which give a better rate of response, a wider spectrum of response, and/or reduced cardiotoxicity. More effective and less toxic agents are widely sought and are a fundamental object of this invention.
Much of the history and prior art of doxorubicin and its anthracycline analogues is found in the article xe2x80x9cAdriamycinxe2x80x9d by David W. Henry, ACS Symposium Series, No. 30, Cancer Chemotherapy, American Chemical Society, pp. 15-57 (1976) and in the book Doxorubicin by Frederico Arcamone, Academic Press, 1981. The derivative AD32 is disclosed in U.S. Pat. No.. 4,035,566, dated Jul. 12, 1977.
5-Iminodaunorubicin is shown in U.S. Pat. No. 4,109,076 which issued on Aug. 22, 1978, to David W. Henry and George L. Tong. The doxorubicin equivalent is shown in xe2x80x9cSynthesis and Preliminary Antitumor Evaluation of 5-Iminodoxorubicinxe2x80x9d, J. Med. Chem. 24, 669 (1981) by Edward M. Acton and George L. Tong. 5-Iminodoxorubicin retained activity with reduced side effects with 5-Iminodoxorubicin showed enhanced activity but required higher dosages.
3xe2x80x2-Deamino-3-(4-morpholinyl)daunorubicin is described in U.S. Pat. No. 4,301,277 issued on Nov. 17. 1981 to Acton et al. It was active at one-fortieth the dose of doxorubicin but gave a substantially identical T/C value (166% vs 160% against P388). This compound and its preparation and properties are also disclosed in xe2x80x9cEnhanced Antitumor Properties of 3xe2x80x2-(4-Morpholinyl) and 3xe2x80x2-(4-Methoxy-1-piperidinyl) Derivatives of 3""Deaminodaunorubicinxe2x80x9d, J. Med. Chem., 25, pp. 18-24 (1982) by Mosher et al.
A general reductive alkylation process for preparing certain new semi-synthetic anthracycline derivatives is described in xe2x80x9cAdriamycin Analogues. 3. Synthesis of N-Alkylated Anthracyclines With Enhanced Efficacy and Reduced Cardiotoxicityxe2x80x9d, J. Med. Chem., 22 pp. 912-918 (1979) by Tong et al.
A group of daunorubicin and doxorubicin derivatives is disclosed in U.S. Pat. No. 4,585,859, issued Apr. 29, 1986. Included in this group are 3xe2x80x2-deamino-3xe2x80x2-(3xe2x80x3-cyano-4xe2x80x3-morpholinyl doxorubicin; 3xe2x80x2-deamino-3xe2x80x2(3xe2x80x3-cyano-4xe2x80x3-morpholinyl)-13-dihydrodoxorubicin; (3xe2x80x2-deamino-3xe2x80x2-(3xe2x80x3-cyano-4xe2x80x3-morpholinyl)-3-dihydrodaunorubicin; and 3xe2x80x2-deamino-3xe2x80x2-(4xe2x80x3-morpholinyl-5-iminodoxorubicin and derivatives thereof which have activity as antitumor agents.
U.S. Pat. No. 4,841,085, Jun. 20, 1989, by one of the present inventors, describes diacetatopropyl phosphoramidic mustard derivatives activatable in vivo by endogenous esterases.
U.S. Pat. No. 4,826,964 issued May 2, 1989 to Acton et al. describes cyanomorpholino doxorubicin which contains an esterified hydroxyl group on the morpholino group. There appears to be little, other than general classification, in common between this compound and those of the present invention.
U.S. Pat. No. 4,755,619 issued Jul. 5, 1988 to Creighton et al. discusses a multifunctional compound which is a derivatized dicarbonylalkyl N-substituted drug which may be activated in vivo by hydrolysis of an ester group. This is indirectly related to the compound of the present invention but is chemically quite different. It is suggested, see column 9, lines 20-30, that the subject compounds and anthracyclines such as doxorubicin may be advantageously used together to treat cancer synergistically while avoiding the cardiotoxicity of the doxorubicin. While there was some analogy in chemical structure and in vivo activation, this reference does not seriously detract from the patentability of the present invention.
The Tsuchiya et al. reference (J. Antibiotics, July 1988, 988-991) describe doxorubicin derivatives with excellent activities against L1210 leukemia and lowered toxicities as compared to doxorubicin. These derivatives, although having ester linkages, are nonanalogous to those of the present invention.
The Acton et al. reference (J. Med. Chem. 1986, 29, 2120-2122) describes cyanomorpholinyl doxorubicin compounds and their properties.
The Horton and Priebe reference (J. Antibiotics, XXXVI, 1211-1215, 1983) describes a range of esterified anthracycline derivatives. None of these derivatives has the bis-acetal substituents of the present invention.
The Tong et al. reference (J. Med. Chem. 8, 912-918, 1979) describes various N-alkyl and N,N-dialkyl anthracyclines and their 13-dihydro derivatives.
The pertinent subject matter of the above references is specifically incorporated herein by reference.
The present invention is a compound having the structure 
where:
anthracycline is doxorubicin, daunorubicin or a derivative thereof;
N is the 3xe2x80x2 nitrogen of daunosamine;
Ra is H or alkyl;
X is O or S, CRc2 or NRc, where Rc is H or alkyl;
Rb is alkyl or aryl;
n is 1 to 6; and
m is 0 to 6.
Ra and Rc are preferably and independently H, methyl, ethyl, propyl or butyl. Rb when an alkyl is preferably methyl, ethyl, propyl or butyl, although other alkyl substituents are usable. The compound of the present invention as described above is activatable in vivo by esterases and spontaneous dehydration to form an aldehyde. The aldehyde may couple to nucleophiles of intracellular macromolecules. The compounds of the present invention are cytotoxically effective in the inhibition of human leukemia myeloma cells.